Cytokine Receptor Heterodimerization

The mechanism of signal initiation by placental lactogens (PLs) has been unclear. In heterologous systems, ruminant PLs can bind to both prolactin receptors (PRLRs) and growth hormone receptors (GHRs) from other species. In homologous systems (i.e., ovine PL binding to ovine PRLR or ovine GHR), ovine PL can act as antagonist for the ovine GHR in transfected cells, and the affinity of PL for the homodimeric receptors does not correlate with physiological activity. One possible explanation for the unusual characteristics of PL activity is that PL would induce heterodimerization of GHRs and PRLRs. Herman et al. demonstrate by gel filtration and surface plasmon resonance that ovine PL can induce heterodimers between the extracellular domains of ovine GHRs and bovine PRLRs. Heterodimers appeared to be functional, on the basis of cotransfection assays in which cotransfection of the ovine PRLR and GHR resulted in enhanced response to ovine PL. Further evidence for functional interaction of the GHR cytoplasmic domain with the PRLR cytoplasmic domain came from activation of signal transduction through chimeras between the extracellular domain of the α or β subunit of granulocyte and macrophage colony-stimulating factor receptor and the intracellular domain of GHR or PRLR. The data provide evidence for a mechanism of generating cytokine-signaling diversity through receptor heterodimerization.